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Review
. 2014;8(2):146-57.
doi: 10.4161/cam.28437.

CCM1 and the second life of proteins in adhesion complexes

Maaike C W van den Berg  1 , Boudewijn M T Burgering  1
Affiliations
Review

CCM1 and the second life of proteins in adhesion complexes

Maaike C W van den Berg et al. Cell Adh Migr. 2014.

Abstract

It is well recognized that a number of proteins present within adhesion complexes perform discrete signaling functions outside these adhesion complexes, including transcriptional control. In this respect, β-catenin is a well-known example of an adhesion protein present both in cadherin complexes and in the nucleus where it regulates the TCF transcription factor. Here we discuss nuclear functions of adhesion complex proteins with a special focus on the CCM-1/KRIT-1 protein, which may turn out to be yet another adhesion complex protein with a second life.

Keywords: CCM1/Krit-1; Rac Rho; adhesion signaling; nuclear translocation; small GTPases; transcription.

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Figures

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Figure 1. A simplified representation of the important mediators of cell–cell and cell–matrix adhesion. The adherens junctions consist of the Claudin and JAM families of transmembrane proteins, which are connected to the actin cytoskeleton via the ZO-family of proteins. Tight junctions consist of the catenin and nectin families of transmembrane proteins, which are connected to the cytoskeleton via the β-catenin interaction to α-catenin. Integrin-mediated cell–cell or cell–matrix interactions at focal adhesion sites is established via interaction of talins and kindlins to actin bundles (1). This can be inhibited by binding proteins such as filamin and ICAP1 to the β-integrin tail (2). For further details, see text.
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Figure 2. Molecular details of CCM1 biological function. Loss of CCM1 results in release of β-catenin from VE-cadherin, and subsequent activation of TCF/LEF-dependent transcription (1). Interaction of ICAP1 to β1-integrins disturbs focal adhesions by preventing binding of talin and kindlin. CCM1 inhibits binding of ICAP1 to β1-integrins and ICAP1 stabilizes CCM1 followed by nuclear translocation of the complex (2). CCM1 is located to the plasma membrane through interaction with the HEG1 transmembrane receptor.
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Figure 3. Dual role of proteins in adhesion complexes and transcription regulation. In absence of wnt signaling, β-catenin is degraded by the APC-destruction complex, whereas in presence of wnt signaling, degradation of β-catenin by APC is prevented and β-catenin activates TCF/LEF-mediated transcription (Left panel). Disruption of E-cadherin signaling by, for example, ADAM10-mediated cleavage of E-cadherin, results in nuclear translocation of β-catenin, and subsequent activation of the Wnt signaling pathway. However, following complete disintegration of the E-cadherin complex, the cytoplasmic domain of E-cadherin, derived after proteolytic cleavage and in addition p120ctn, may also translocate to the nucleus (Right panel). Combined or in isolation this nuclear shuttling of E-cadherin complex proteins may have different biological outcome. Multiple signals, like stress signals can result in nuclear localization of FAK, a key component of integrin signaling (left panel).
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Figure 4. (A) Loss of CCM1 (depicted with a red cross in the figure) results in activation of Rho signaling (1), inhibition of DLL4-Notch signaling (2), nuclear localization of β-catenin (3), disruption of focal adhesions (indicated by red cross through integrins) as a result of ICAP binding (4), and decreased FOXO protein levels, resulting in increased ROS levels (5). (B) Suggested model in a situation where cadherin signaling is disrupted (depicted by a red cross through cadherin). See text for more details.
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